Thymic antigen-presenting cells (APCs) such as dendritic cells and medullary thymic epithelial cells (mTECs) use distinct strategies of self-antigen expression and presentation to mediate central tolerance. The thymus also harbors B cells; whether they also display unique tolerogenic features and how they genealogically relate to peripheral B cells is unclear. Here, we found that Aire is expressed in thymic but not peripheral B cells. Aire expression in thymic B cells coincided with major histocompatibility class II (MHCII) and CD80 upregulation and immunoglobulin class-switching. These features were recapitulated upon immigration of naive peripheral B cells into the thymus, whereby this intrathymic licensing required CD40 signaling in the context of cognate interactions with autoreactive CD4(+) thymocytes. Moreover, a licensing-dependent neo-antigen selectively upregulated in immigrating B cells mediated negative selection through direct presentation. Thus, autoreactivity within the nascent T cell repertoire fuels a feed forward loop that endows thymic B cells with tolerogenic features.

Drug tolerance is the basis for acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) including osimertinib, through mechanisms that still remain unclear. Here, we show that while AXL-low expressing EGFR mutated lung cancer (EGFRmut-LC) cells are more sensitive to osimertinib than AXL-high expressing EGFRmut-LC cells, a small population emerge osimertinib tolerance. The tolerance is mediated by the increased expression and phosphorylation of insulin-like growth factor-1 receptor (IGF-1R), caused by the induction of its transcription factor FOXA1. IGF-1R maintains association with EGFR and adaptor proteins, including Gab1 and IRS1, in the presence of osimertinib and restores the survival signal. In AXL-low-expressing EGFRmut-LC cell-derived xenograft and patient-derived xenograft models, transient IGF-1R inhibition combined with continuous osimertinib treatment could eradicate tumors and prevent regrowth even after the cessation of osimertinib. These results indicate that optimal inhibition of tolerant signals combined with osimertinib may dramatically improve the outcome of EGFRmut-LC.

The identity of peripheral Aire-expressing cells remains poorly understood. This study shows that Aire-expressing cells in peripheral lymph nodes exhibit typical ILC3 characteristics. These cells display potent APC features, suggesting a function in the control of T cell responses.

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Near‐infrared (NIR) bioimaging is attracting a lot of attention due to the absence of strong scattering and color fading of the phosphors, which can provide long‐term and deep imaging. For fluorescence bioimaging (FBI) in the NIR region, rare‐earth‐doped ceramic nanoparticles can be one of the best candidates. For the delivery of the ceramic particles to the biological imaging target, liposome‐encapsulating the ceramic phosphor is proposed. Liposome‐encapsulated, Er‐doped Y2O3 nanoparticles were prepared as fluorescent probes for NIR bioimaging. Their surface was modified with PEG, biotin, anionic, and cationic agents. The dispersion, surface charge, and specific interactions of the surface‐modified liposomes were characterized. Microscopic and macroscopic NIR bioimages were demonstrated by injecting the liposome‐encapsulated, Er‐doped Y2O3 nanoparticles into the body of a mouse through the blood vessels. The NIRfluorescence images of the mouse organs are presented.